Summary of Work: The tools of molecular genetics provide fresh opportunities to explore environmental toxins, especially toxins that affect genetically-susceptible people. We recently began a large population-based case-control study of cleft lip and palate. This study is being conducted in Norway, which has one of the highest reported rates of facial clefts in the world, and which also has highly organized birth registries. Mothers provide careful information regarding occupational and household exposures, diet and other factors during pregnancy. We also collect genetic material from controls, cases, and their parents. Scheduled for completion in 2001, this study will provide the largest and most complete collection of data ever obtained for this common birth defect. To prepare for the analysis of these data, we have been working on theoretical aspects of genetic studies and the analysis of gene- environment interaction. We have provided a statistical method that can help detect the presence of environ-mental teratogens that cause more than one kind of birth defect. Also, we have explored the possibility that "disease" genes (i.e. gene allelic variants that are associated with adult chronic disease) might have adaptive effects that are beneficial at earlier stages of life. Finally, we have developed a new method for the study of gene alleles that work through the maternal genotype. It is biologically plausible that maternal genes can affect fetal development by effects on the intrauterine environment (in contrast to effects through the fetal inheritance of the maternal allele). This possibility has been previously recognized, but no methods have been available for the detection of such effects among affected offspring and biological parents (i.e. without other controls). We provide such a method, which has a number of advan- tages over such methods as the TDT (transmission/disequilibrium test). This method was developed in the context of the study of birth defects, but it may also be useful for any illness with origins in the intrauterine environment.